ANTIBIOTICS FOR

URINARY TRACT
INFECTIONS
NAN I MAHARANI

D E PA RT M E N T O F P H A R M AC O LO GY & T H E RA P E U T I C S
FAC U LT Y O F M E D I C I N E D I P O N E G O R O U N I V E R S I T Y
2016
Introduction
Urinary tract infections: infections of the urethra (urethritis), bladder
(cystitis), ureters (ureteritis), and kidney ( pyelonephritis).
Common pathogens: Staphylococcus saprophyticus, Klebsiella species,
Proteus mirabilis, Enterococcus faecalis, etc.
Introduction
SULFONAMIDES
TRIMETHOPRIM + SULFAMETOXAZOLE
QUINOLONES
CEPHALOSPORINS
SULFONAMIDES
 Sulfonamides
Bacteriostatic effects
Antimicrobial spectrum:
- Streptococcus pyogenes
- Streptococcus pneumoniae
- Haemophilus influenza
- Haemophilus ducreyi
- Nocardia
- Actinomycetes
- Chlamydia trachomatis
Except: Rickettsia
Mechanism of action
Pteridine + PABA

sulfonamide
Dihyropteroate synthase

Dihydrofolic acid
NADPH

Dihydrofolate reductase
NADP

Tetrahydrofolic acid

Purines

DNA
Pharmacokinetics
Absorption, Fate, Excretion

- Absorbed rapidly and efficiently from the GI tract

- Peak plasma levels are achieved within 2-6 h

- Widely distributed, incld.CNS, placenta & fetus

- Dose must be reduced in significant renal failure

- Divided into classes based on rapidity with which they are

absorbed and excreted:
Classifications
CLASS SULFONAMIDES SERUM T1/2 (h)

Absorbed & excreted Sulfisoxazole 5-6

rapidly Sulfamethoxazole 11
Sulfadiazine
10
Poorly absorbed- Sulfasalazine -
active in bowel lumen
Topically used Sulfacetamide -
Silver sulfadiazine -
Long-acting Sulfadoxine 100-230
Adverse effects & drug
interactions
Untoward reactions to sulfonamides (accounted for ~5%):
- The risk of crystaluria
- Disorders of the hematopoietic system
- Agranulocytosis
- Hypersensitivity reactions (cross-allergenic with other
sulfa drugs, such as diuretic (furosemide, thiazide), anti-
diabetic (sulfonylurea), etc.
Drug interactions:
- Oral anticoagulants
- Hypoglycemic
Trimethoprim-
Sulfamethoxazole
Cotrimoxazole
Synergistic combination
Trimethroprim : Sulfamethoxazole = 1 : 5 (160 mg : 800 mg)
Antimicrobial spectrum: most gram-negative and gram-
positive bacteria
Less resistance issues compared to either agents alone
Mechanism of action
Pteridine + PABA

sulfonamide
Dihyropteroate synthase

Dihydrofolic acid
NADPH

Dihydrofolate reductase trimethoprim

NADP

Tetrahydrofolic acid

Purines

DNA
Untoward effects
Be careful in patients with folate deficiency: leukopenia,
thrombocytopenia
Patients with AIDS: hypersensitivity reactions (rash, neutropenia, SSJ,
pulmonary infiltrate).
Dermatological reactions: rash to exfoliative dermatitis
Mild & transient jaundice
CNS reactions: headache, depression, hallucination
Hematological reactions: anemia, coagulation disorders,
granulocytopenia, etc
Resistance
Results from mutations that:
1. Cause overproduction of PABA
2. Cause production of folic acid-synthesizing enzyme
3. Impair permeability to the sulfonamide
QUINOLONES
QUINOLONES
Mechanism of action:
- Inhibit bacterial DNA synthesis by inhibiting DNA
gyrase and topoisomerase IV rapid cell death

Bactericidal
Pharmacokinetics
Well absorbed (bioavailability 80-95%)
Widely distributed
Serum half-lives: 3-10 h
Levofloxacin, Gemifloxacin, Gatifloxacin & Moxifloxacin: once-daily
dosing
Most fluoroquinolones are eliminated by renal, except Moxifloxacin
Mechanism of
action
Classification
Quinolones (1st generation)
Highly protein bound, did not achieve systemic
antibacterial levels.
Mostly used in UTIs
Fluoroquinolones (2nd and 3rd)
Modified 1st generation quinolones
Not highly protein bound
Wide distribution to urine and other tissues
Classification
Generation Drug Names Spectrum
nalidixic acid Gram- but not Pseudomonas
1st cinoxacin species

norfloxacin Gram- (including Pseudomonas

ciprofloxacin species), some Gram+ (S.
2nd aureus) and some atypicals
enoxacin
ofloxacin
levofloxacin Same as 2nd generation with
sparfloxacin extended Gram+ and atypical
moxifloxacin coverage
3rd
gemifloxacin
Mechanisms of
resistance
Mechanisms of resistance:
Specific mutations in gyrase and/or topoisomerase
IV
Plasmid-mediated : E.coli (can be transmitted
horizontally)
Chromosome-mediated
Decreased drug penetration: Pseudomonas, E. coli
Drug interactions
absorption: Al3+, Mg2+, and Ca2+ antacids
CYP450 inhibition potential drug interactions for
ciprofloxacin
(Ex) can increase warfarin exposure (real
changes in INR are rare, but monitor)
Adverse effects
GI: Nausea, vomiting
CNS: HA, dizziness, confusion, insomnia, delerium,
hallucinations, seizure (rare)
Cardiovascular: Long QT, Torsades de pointes (rare)
Musculoskeletal: damage growing cartilage (cause
arthropathy) C.I for <18 y, Rupture of tendon (rare)
Neurologic: Polyneuropathy (rare)
 Fluoroquinolones &
Long-QTS
QT interval (420440 ms in males and 440460 ms in females)

Cardiology 2011;120:103110
Ciprofloxacin
Administration [Usual Dosage]: IV, PO [500 750 mg q 8-12h]
Spectrum: Gram- aerobic rods, and other atypicals.
Unique Qualities:
Binds divalent cations (i.e. Ca & Mg) which decreases absorption
-- Increased effects of warfarin
ADRs
QTC prolongation, torsades de pointes, arrhythmias
Nausea, GI upset
Interstitial nephritis
Levofloxacin
Administration [Usual Dosage]: IV, PO [500-750 mg q24h]
Spectrum: Gram-, Gram+
Unique Qualities:
Binds divalent cations (i.e. Ca & Mg) which decreases absorption
ADRs
Blood glucose disturbances in DM patients
QTC prolongation, torsades de pointes, arrhythmias
Nausea, GI upset
Interstitial nephritis
Moxifloxacin
Administration [Usual Dosage]: IV, PO [400mg q24h]
Spectrum: Gram-, Gram+, atypicals, gram-negative anaerobes
Unique Qualities:
Binds divalent cations (i.e. Ca & Mg) which decreases absorption
Safety and efficacy not established in patients <18 y.o.

ADRs
Blood glucose disturbances in DM patients
QTC prolongation, torsades de pointes, arrhythmias
Nausea, GI upset
Interstitial nephritis
NITROFURANTOIN
Antimicrobial activity
E. coli, enterococci
Bacteriostatic for most susceptible microorganisms at </= 32 g/mL, or
less
Bactericidal at >/= 100 g/mL
Antibacterial activity is higher in acidic urine
Pharmacokinetics
Absorbed rapidly and completely from the GI tract
~40% excreted unchanged into the urine
The average dose yields a concentration in urine of ~200 g/mL
In patients with impaired glomerular function, the efficacy is decreased,
and the toxicity is increased
Doses
Adults: 50-100 mg 4x a day (microcrystalline form = 100 mg every 12 h),
for 7 days
Children: 5-7 mg/kg, or 1 mg/kg for long-term therapy
Should not exceed 14 days
Untoward effects
Nausea, vomiting, diarrhea
Hypersensitivity reactions: chills, fever, leukopenia, granulocytopenia,
hemolytic anemia, cholestatic jaundice, hepatocellular damage.
Chronic active hepatitis
Acute pneumonitis
Headache, vertigo, dizzines
Neuropathies in patients with impaired renal function and long-
continued treatment
CEPHALOSPORIN
Cephalosporins
1st Gram (+), except MRS

2nd spektrum lebih luas Gr (-)

3rd spektrum Gr (-) Gr (+)

Serious Gram negative infections
4th cefepime Anti-Pseudomonal coverage
Spektrum Gr (-)/Gr (+) baik
 CLASSIFICATION
1st Gen 2nd Gen 3rd
Gen 4th Gen
Cefadroxil * Cefaclor * Cefdinir Cefepime
Cefazolin Cefamandole Cefoperaxone

Cefelixin * Cefonicid Cefotaxime

Cephalothin Ceforanide Ceftazidime

Cephaprin Cefotetan Ceftibuten

Cephradine * Cefoxitin Ceftizoxime

Cefuroxime
Ceftriaxone
moxalactam
* Oral Agent
1st generation
cephalosporins:
Cephalothin, Cefazolin, Cefalexin, Cefadroxil.
Sensitive Resistant
Gram (+) cocci, except Pseudomonas
MRS aeruginosa
Gram (-): E.coli, Enterobacter
Klebsiella pneumoniae,
Proteus mirabilis

Anaerobic cocci, except Proteus sp.

Bacteroides fragilis
1st generation
cephalosporins:
Absorbed from the gut to a variable extent
Urine concentration is very high, but in most tissues levels are variable
and generally lower than in serum
Excretion is mainly by glomerular & tubular secretion reduce dosage
in patients with impaired renal function
Cephadroxil: 0.5-1 g twice daily, Cephalexin 0.25-0.5 g four times daily
Oral cephalosporin can be used for UTI, cellulitis/soft tissue abcess, but
not for serious systemic infection
Cefazolin (parenteral cephalosporin): surgical prophylaxis, staph or strep
infection. Cant be used for meningitis.
2nd generation
cephalosporins:
Cefuroxime, Cefamandole, Cefoxitin, Cefaclor,
Cefotetan.
Sensitive Resistant
(same as 1st generation) (same as 1st generation)
Extended gram (-) coverage
H.influenza
2nd generation
cephalosporins:
Cefaclor, Cefuroxime: 10-15 mg/kgBB/day in 2-4 divided dose
Parenteral Cefuroxime: 0.75-1.5 g every 8 h (iv), crosses the BBB, but
should not be used for meningitis
Dosage adjustment is needed in renal failure
 3rd generation
cephalosporins:
Moxalactam, Cefaperazone, Ceftazidirne,
Ceftriaxone.
Sensitive Resistant
(same as 1st & 2nd gen, with Enterobacter
extended gram(-) coverage)
B-lactamase-producing
Haemophilus & Neisseria
P.aeruginosa (Ceftazidime,
Cefoperazone)
B. fragilis (Ceftixoime,
moxalactam)
3rd generation
cephalosporins:
Penetrates body fluids and tissues well including cerebrospinal fluid
(except cefoperazone & oral cephalosporins)
Half-lives & dosing interval varies greatly
Excretion of cefoperazone & ceftriaxone is mainly through the biliary
tract no dosage adjustment is required in renal insufficiency. The
others: excreted by the kidney.
4th generation
cephalosporin:
E.g. cefepime
Comparable to third-generation but more resistant to
some betalactamases.

Sensitive Resistant
(same as 1st & 2nd gen, with
extended gram(-) coverage)
P aeruginosa
Enterobacter
Adverse effects
Hypersensitivity reactions.
Those who allergic to penicillin may tolerate cephalosporins, however,
do not give it to patients who with a history of anaphylaxis to penicillin.
Nephrotoxicity and intolerance to alcohol (disulfiram like reaction) has
been reported. (cefamandole, cefotetan, moxalactam, cefoperazone )
Diarrhea may occur with oral forms. Many second and particularly third
generation cephalosporins are ineffective against Gram-positive
organisms, especially methicillin resistant Staphylococci and Enterococci.
During treatment with such drugs, these resistant organisms as well as
fungi, often proliferate and may induce superinfection.
Hyperprothrombinemia, Thrombocytopenia, Platelet dysfunction.
Administration of vitamin K (10mg) twice a week can prevent this.
Further readings:
Basic & Clinical Pharmacology (Bertram G Katzung): Sulfonamides,
Trimethoprim, and Quinolones.
The Pharmacological Basis of Therapeutics (Goodman & Gilmans):
Sulfonamides, Trimethoprim-Sulfamethoxazole, Quinolones, and Agents
for Urinary Tract Infections.
Questions, discussions, critiques,
suggestions:

maharani.nani@gmail.com
Thank you